Abstract
Pegylated liposomal doxorubicin (PLD) is a liposome-encapsulated form of doxorubicin with equivalent efficacy and less cardiotoxicity. This phase 2 study evaluated the efficacy and safety of the PLD-containing CHOP regimen in newly diagnosed patients with aggressive peripheral T-cell lymphomas (PTCL).
Patients received PLD, cyclophosphamide, vincristine/vindesine, plus prednisone every 3 weeks for up to 6 cycles. The primary endpoint was the objective response rate at the end of treatment (EOT).
From September 2015 to January 2017, 40 patients were treated. At the EOT, objective response was achieved by 82.5% of patients, with 62.5% complete response. As of the cutoff date (September 26, 2023), median progression-free survival (mPFS) and overall survival (mOS) were not reached (NR). The 2-year, 5-year, and 8-year PFS rates were 55.1%, 52.0%, and 52.0%. OS rate was 80.0% at 2 years, 62.5% at 5 years, and 54.3% at 8 years. Patients with progression of disease within 24 months (POD24) had worse prognosis than those without POD24, regarding mOS (41.2 months vs NR), 5-year OS (33.3% vs 94.4%), and 8-year OS (13.3% vs 94.4%). Common grade 3-4 adverse events were neutropenia (87.5%), leukopenia (80.0%), anemia (17.5%), and pneumonitis (17.5%).
This combination had long-term benefits and manageable tolerability, particularly with less cardiotoxicity, for aggressive PTCL, which might provide a favorable benefit-risk balance.
Chinese Clinical Trial Registry, ChiCTR2100054588; IRB Approved: Ethics committee of Fudan University Shanghai Cancer Center (Date 2015.8.31/No. 1508151-13.
With an 8-year follow-up, the PLD-containing CHOP regimen had long-term benefits in PTCL, with 8-year PFS and OS rates of 52.0% and 54.3%.
The PLD-containing CHOP regimen was associated with less cardiotoxicity compared with CHOP/CHOP-like regimens and was generally manageable.
Based on these impressive long-term results, the combination regimen may serve as a reasonable first-line approach with a favorable benefit-risk balance for aggressive PTCL.
Discussion
PTCL is a rare and heterogeneous hematologic malignancy, with dismal outcomes. Despite much efforts (eg, targeted therapy and immunotherapy) in improving efficacy, the CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CHOP-like regimens remain the preferred first-line therapy option for the general population with PTCL. Nevertheless, doxorubicin is associated with cumulative and dose-dependent cardiotoxicity, resulting in increased risks of mortality. PLD is a liposome-encapsulated form of doxorubicin with equivalent efficacy and less cardiotoxicity. With the goal of getting a favorable benefit-risk balance and based on our phase 1 dose-escalation study, we designed a prospective, single-arm, phase 2 study to evaluate the efficacy and safety of 40 mg/m2 PLD as an alternative for doxorubicin in CHOP regimen for aggressive PTCL.
From September 2015 to January 2017, 40 patients received at least one dose of protocol therapy. At the time of data cutoff (September 26, 2023), 30 (75.0%) patients completed the planned treatment schedule. At the end of treatment (EOT), objective response was achieved in 82.5% (95% CI, 67.2-92.7) of patients, with 62.5% complete response and 20.0% partial response (PR). Median duration of response (DoR) of responders was not reached, with a 2-year DoR rate of 58.7% (95% CI, 44.6-77.2), both 5-year and 8-year DoR rates of 55.8% (95% CI, 41.6-74.7). With a median follow-up of 7.4 years (95% CI, 7.1-7.9), mPFS was NR (Figure 1A). The estimated PFS rate of the overall population was 55.1% (95% CI, 40.5-74.9) at 2 years, and both 52.0% (95% CI, 37.5-72.2) at 5 and 8 years, respectively. Based on 18 deaths, the median OS was also NR due to insufficient events (Figure 1B), with 2-year, 5-year, and 8-year OS rates of 80.0% (95% CI, 68.5-93.4), 62.5% (95% CI, 49.2-79.5), and 54.3% (95% CI, 40.7-72.5). The prognostic significance of progression of disease within 24 months (POD24) has been identified for patients with newly diagnosed PTCL. Here, POD24 was observed in 15 (45.5%) of 33 patients and was found to be associated with poor OS (non-POD24 vs POD24: NR vs 41.2 months; P < .001). Treatment-related adverse events of any grade occurred in all 40 (100%) patients, with ≥grade 3 events being reported in 36 (90%) and serious events in 6 (15%). From baseline to the EOT, 30 patients exhibited different degrees of left ventricular ejection fraction (LVEF) decline, with a mean of 7.2% (range, 1.0%-19.0%; SD, 4.3%). The LVEF decline of ≥10% was observed in 6 patients (15%), of which 2 (5%) had a resting LVEF of <50%. Besides, 13 (43.3%) patients displayed a subsequent recovery of LVEF.
Kaplan-Meier curves in the overall population. (A) Progression-free survival. PFS analysis was performed by censoring patients who received non-study antitumor therapies prior to progression at the time of starting new antitumor therapies. With 16 disease progression or death occurring, the median PFS was not reached at the data cutoff, with estimated PFS rates of 55.1% (95% CI, 40.5-74.9) at 2 years, and both 52.0% (95% CI, 37.5-72.2) at 5 and 8 years. (B) Overall survival. Based on 18 deaths, the median OS of all patients was not reached due to insufficient events, with 2-year, 5-year, and 8-year OS rates of 80.0% (95% CI, 68.5-93.4), 62.5% (95% CI, 49.2-79.5), and 54.3% (95% CI, 40.7-72.5).
| Trial Information | |
|---|---|
| Disease | Peripheral T-cell lymphoma |
| Stage of disease/treatment | Stage 1-4/newly diagnosed |
| Prior therapy | None |
| Type of study | Prospective, open-label, single-arm, phase 2 study |
| Primary endpoint | Objective response rate (ORR) at the EOT |
| Secondary endpoints | Progression-free survival (PFS), overall survival (OS), DoR, and safety |
| Trial Information | |
|---|---|
| Disease | Peripheral T-cell lymphoma |
| Stage of disease/treatment | Stage 1-4/newly diagnosed |
| Prior therapy | None |
| Type of study | Prospective, open-label, single-arm, phase 2 study |
| Primary endpoint | Objective response rate (ORR) at the EOT |
| Secondary endpoints | Progression-free survival (PFS), overall survival (OS), DoR, and safety |
| Trial Information | |
|---|---|
| Disease | Peripheral T-cell lymphoma |
| Stage of disease/treatment | Stage 1-4/newly diagnosed |
| Prior therapy | None |
| Type of study | Prospective, open-label, single-arm, phase 2 study |
| Primary endpoint | Objective response rate (ORR) at the EOT |
| Secondary endpoints | Progression-free survival (PFS), overall survival (OS), DoR, and safety |
| Trial Information | |
|---|---|
| Disease | Peripheral T-cell lymphoma |
| Stage of disease/treatment | Stage 1-4/newly diagnosed |
| Prior therapy | None |
| Type of study | Prospective, open-label, single-arm, phase 2 study |
| Primary endpoint | Objective response rate (ORR) at the EOT |
| Secondary endpoints | Progression-free survival (PFS), overall survival (OS), DoR, and safety |
Additional details of endpoints or study design
Study design
The prospective, open-label, single-arm, single-center, phase 2 study (Chinese Clinical Trial Registry, ChiCTR2100054588) was carried out to evaluate the efficacy and safety of PLD, cyclophosphamide, vincristine/vindesine, and prednisone in subjects with newly diagnosed aggressive PTCL. This study was performed following the Declaration of Helsinki and clinical practice guidelines and was approved by the ethics committee of Fudan University Shanghai Cancer Center (number, 1508151-13). All included subjects were fully aware of the protocol and submitted written informed consent.
Patient eligibility
Patients aged 18-75 years with histologically confirmed treatment-naïve aggressive PTCL (except natural killer/T-cell lymphoma) according to the World Health Organization classification were eligible for this study. Additional criteria of enrollment included an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, a life expectancy of at least 6 months, at least one measurable lesion, and baseline left ventricular ejection fraction (LVEF) of ≥50%. Patients were also required to have adequate organ function of bone marrow, liver, and kidney.
Patients with primary or secondary central nervous system involvement, other malignant tumors (except cured cervical cancer or basal cell carcinoma of the skin), heart disease, previous severe chronic skin diseases, poorly controlled hypertension or diabetes, severe active infection, previous allergic asthma or severe allergic disease, or mental disorders were ineligible for this study. Patients who had received organ transplants, as well as pregnant or lactating females were also excluded.
Procedures
Eligible patients were treated with intravenous (i.v.) PLD (Duomeisu, 40 mg/m2, CSPC Ouyi Pharmaceutical Group Co., Ltd.), cyclophosphamide (750 mg/m2), and vincristine (1.4 mg/m2, maximum 2 mg/m2) or vindesine (2 mg/m2, maximum 4 mg/m2) on day 1, plus oral prednisone (50 mg, twice-daily) on days 1-5 of each cycle. Treatment cycles were repeated every 3 weeks for up to 6 cycles, until intolerable toxicity, loss of tumor response, or death. Due to a transient shortage of vincristine in China, some patients were administered vindesine instead of vincristine. Suspension, discontinuation, and dose reduction of chemotherapy drugs were allowed according to the severity of any adverse events (AEs) that occurred in the previous course. Antiemetic therapy with 5-hydroxytryptamine 3 receptor antagonists was routinely administered. Prophylactic granulocyte-colony stimulating factors (G-CSF), thrombopoietin rather than interleukin-11, and component transfusion were allowed. The use of dexrazoxane was prohibited. Besides, consolidation with autologous stem cell transplantation (auto-SCT) after first-line therapy or maintenance therapy after objective response from first-line therapy was not allowed.
Treatment response was assessed at baseline and the end of cycles 2, 4, and 6 using enhanced computed tomographic (CT) scans according to the standardized response criteria for NHLs.1 AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0. Prespecified AE of special interest was cancer therapy-related cardiac dysfunction (CTRCD), which was defined as a resting LVEF <50% and an absolute reduction in LVEF ≥10%, or the occurrence of signs or symptoms of congestive heart failure according to previous studies.2 LVEF was assessed by radionuclide angiography at screening and at the end of cycle 2, cycle 4, and cycle 6. In long-term follow-up, complete blood count, liver and kidney function, serum lactate dehydrogenase (LDH), and imaging examination by enhanced CT scan were performed every 3 months during the first 2 years after completion of study treatment, and every 6 months thereafter until patients experienced disease progression, death, or the initiation of a new treatment, whichever came first.
Endpoints
The primary endpoint was the ORR at the EOT, which was defined as the proportion of patients who achieved complete response (CR; complete response or unconfirmed complete response) or PR at the EOT as per the Standardize response criteria for non-Hodgkin’s lymphomas: International Working Group.1 Secondary endpoints included PFS (defined as the time from enrollment to disease progression or death from any cause), OS (defined as the time from enrollment to death from any cause), DoR (defined as the time from onset of response to disease progression), and safety.
The outcome according to POD24 status was evaluated as a post hoc exploratory endpoint. POD24 was defined as the first documented relapse or progression of the disease within 24 months after initiation of treatment. Patients were not evaluable for POD24 if they were censored or had died within 24 months without progression of the disease.
Statistical analysis
The sample size calculation of this phase 2 study was based on ORR considerations. According to the historical ORR data (54.4%) of CHOP regimen in Chinese patients with PTCL,3 it is assumed that an ORR of 55% or less is considered unacceptable in this study. We estimated that a target ORR of 77% with PLD plus COP regimen is considered to have statistical significance, based on the mean value of maximum historical ORR (75% and 79%) with CHOP regimen.4,5 With this assumption and a dropout rate of 10%, approximately 40 patients would provide a power of 80% at a 2-sided type I error of 5%.
Efficacy was primarily analyzed in the full analysis set, which comprised all patients who received at least one dose of chemotherapy drugs. Safety was analyzed in the safety analysis set, which comprised all patients who received at least one dose of chemotherapy drugs. The ORR was summarized descriptively, along with the exact 95% CI. The Clopper-Pearson method was used to calculate the 95% CI for ORR. The PFS, OS, and DoR were estimated using Kaplan-Meier curves. PFS analysis was performed by censoring patients who received non-study antitumor therapies prior to progression at the time of starting new antitumor therapies. For the analysis of OS, data for patients who were alive or who were lost to follow-up were censored at the time of the last contact. The OS of the POD24 group and the non-POD24 group were compared using the log-rank test. Safety was analyzed descriptively. All analyses were performed with R Statistical Language (version 4.2.0), and the significance level was set at P < .05.
| Drug Information | |
|---|---|
| Drug 1 | |
| Generic/working name | Pegylated liposomal doxorubicin |
| Company name | CSPC Ouyi Pharmaceutical Group Co., Ltd. |
| Drug type | Cytotoxic agents |
| Drug class | Anthracyclines |
| Dose | 40 |
| Unit | mg/m2 |
| Route | i.v. |
| Schedule of administration | Administered on day 1 every 3 weeks for up to 6 cycles |
| Drug 2 | |
| Generic/working name | Cyclophosphamide |
| Company name | Baxter |
| Drug type | Cytotoxic agents |
| Drug class | Alkylating agents |
| Dose | 750 |
| Unit | mg/m2 |
| Route | i.v. |
| Schedule of administration | Administered on day 1 every 3 weeks for up to 6 cycles |
| Drug 3 | |
| Generic/working name | Vincristine or vindesine |
| Company name | Vincristine (Shenzhen Main Luck Pharmaceuticals Inc.) Vindesine (Hangzhou Minsheng Pharmaceutical Co., Ltd.) |
| Drug type | Cytotoxic agents |
| Drug class | Vinca alkaloids |
| Dose | Vincristine (1.4 mg/m2, maximum 2 mg/m2) Vindesine (2 mg/m2, maximum 4 mg/m2) |
| Unit | mg/m2 |
| Route | i.v. |
| Schedule of administration | Administered on day 1 every 3 weeks for up to 6 cycles |
| Drug 4 | |
| Generic/working name | Prednisone |
| Company name | Tianjin Jinjin Pharmaceutical Co., Ltd. |
| Drug type | Glucocorticoid |
| Drug class | Corticosteroids |
| Dose | 50 |
| Unit | mg |
| Route | Oral |
| Schedule of administration | Administered on days 1-5 every 3 weeks for up to 6 cycles |
| Drug Information | |
|---|---|
| Drug 1 | |
| Generic/working name | Pegylated liposomal doxorubicin |
| Company name | CSPC Ouyi Pharmaceutical Group Co., Ltd. |
| Drug type | Cytotoxic agents |
| Drug class | Anthracyclines |
| Dose | 40 |
| Unit | mg/m2 |
| Route | i.v. |
| Schedule of administration | Administered on day 1 every 3 weeks for up to 6 cycles |
| Drug 2 | |
| Generic/working name | Cyclophosphamide |
| Company name | Baxter |
| Drug type | Cytotoxic agents |
| Drug class | Alkylating agents |
| Dose | 750 |
| Unit | mg/m2 |
| Route | i.v. |
| Schedule of administration | Administered on day 1 every 3 weeks for up to 6 cycles |
| Drug 3 | |
| Generic/working name | Vincristine or vindesine |
| Company name | Vincristine (Shenzhen Main Luck Pharmaceuticals Inc.) Vindesine (Hangzhou Minsheng Pharmaceutical Co., Ltd.) |
| Drug type | Cytotoxic agents |
| Drug class | Vinca alkaloids |
| Dose | Vincristine (1.4 mg/m2, maximum 2 mg/m2) Vindesine (2 mg/m2, maximum 4 mg/m2) |
| Unit | mg/m2 |
| Route | i.v. |
| Schedule of administration | Administered on day 1 every 3 weeks for up to 6 cycles |
| Drug 4 | |
| Generic/working name | Prednisone |
| Company name | Tianjin Jinjin Pharmaceutical Co., Ltd. |
| Drug type | Glucocorticoid |
| Drug class | Corticosteroids |
| Dose | 50 |
| Unit | mg |
| Route | Oral |
| Schedule of administration | Administered on days 1-5 every 3 weeks for up to 6 cycles |
| Drug Information | |
|---|---|
| Drug 1 | |
| Generic/working name | Pegylated liposomal doxorubicin |
| Company name | CSPC Ouyi Pharmaceutical Group Co., Ltd. |
| Drug type | Cytotoxic agents |
| Drug class | Anthracyclines |
| Dose | 40 |
| Unit | mg/m2 |
| Route | i.v. |
| Schedule of administration | Administered on day 1 every 3 weeks for up to 6 cycles |
| Drug 2 | |
| Generic/working name | Cyclophosphamide |
| Company name | Baxter |
| Drug type | Cytotoxic agents |
| Drug class | Alkylating agents |
| Dose | 750 |
| Unit | mg/m2 |
| Route | i.v. |
| Schedule of administration | Administered on day 1 every 3 weeks for up to 6 cycles |
| Drug 3 | |
| Generic/working name | Vincristine or vindesine |
| Company name | Vincristine (Shenzhen Main Luck Pharmaceuticals Inc.) Vindesine (Hangzhou Minsheng Pharmaceutical Co., Ltd.) |
| Drug type | Cytotoxic agents |
| Drug class | Vinca alkaloids |
| Dose | Vincristine (1.4 mg/m2, maximum 2 mg/m2) Vindesine (2 mg/m2, maximum 4 mg/m2) |
| Unit | mg/m2 |
| Route | i.v. |
| Schedule of administration | Administered on day 1 every 3 weeks for up to 6 cycles |
| Drug 4 | |
| Generic/working name | Prednisone |
| Company name | Tianjin Jinjin Pharmaceutical Co., Ltd. |
| Drug type | Glucocorticoid |
| Drug class | Corticosteroids |
| Dose | 50 |
| Unit | mg |
| Route | Oral |
| Schedule of administration | Administered on days 1-5 every 3 weeks for up to 6 cycles |
| Drug Information | |
|---|---|
| Drug 1 | |
| Generic/working name | Pegylated liposomal doxorubicin |
| Company name | CSPC Ouyi Pharmaceutical Group Co., Ltd. |
| Drug type | Cytotoxic agents |
| Drug class | Anthracyclines |
| Dose | 40 |
| Unit | mg/m2 |
| Route | i.v. |
| Schedule of administration | Administered on day 1 every 3 weeks for up to 6 cycles |
| Drug 2 | |
| Generic/working name | Cyclophosphamide |
| Company name | Baxter |
| Drug type | Cytotoxic agents |
| Drug class | Alkylating agents |
| Dose | 750 |
| Unit | mg/m2 |
| Route | i.v. |
| Schedule of administration | Administered on day 1 every 3 weeks for up to 6 cycles |
| Drug 3 | |
| Generic/working name | Vincristine or vindesine |
| Company name | Vincristine (Shenzhen Main Luck Pharmaceuticals Inc.) Vindesine (Hangzhou Minsheng Pharmaceutical Co., Ltd.) |
| Drug type | Cytotoxic agents |
| Drug class | Vinca alkaloids |
| Dose | Vincristine (1.4 mg/m2, maximum 2 mg/m2) Vindesine (2 mg/m2, maximum 4 mg/m2) |
| Unit | mg/m2 |
| Route | i.v. |
| Schedule of administration | Administered on day 1 every 3 weeks for up to 6 cycles |
| Drug 4 | |
| Generic/working name | Prednisone |
| Company name | Tianjin Jinjin Pharmaceutical Co., Ltd. |
| Drug type | Glucocorticoid |
| Drug class | Corticosteroids |
| Dose | 50 |
| Unit | mg |
| Route | Oral |
| Schedule of administration | Administered on days 1-5 every 3 weeks for up to 6 cycles |
| Patient Characteristics | |
|---|---|
| Number of patients | |
| Male | 25 (62.5%) |
| Female | 15 (37.5%) |
| Stage | |
| 1 | 3 (7.5%) |
| 2 | 9 (22.5%) |
| 3 | 10 (25.0%) |
| 4 | 18 (45.0%) |
| Age (years), median (range) | 55.0 (47.8-61.0) |
| Number of prior systemic therapies: median | 0 |
| Performance status: ECOG | |
| 0: 11 (27.5%) | |
| 1: 29 (72.5%) | |
| 2: 0 | |
| 3: 0 | |
| 4: 0 | |
| Patient Characteristics | |
|---|---|
| Number of patients | |
| Male | 25 (62.5%) |
| Female | 15 (37.5%) |
| Stage | |
| 1 | 3 (7.5%) |
| 2 | 9 (22.5%) |
| 3 | 10 (25.0%) |
| 4 | 18 (45.0%) |
| Age (years), median (range) | 55.0 (47.8-61.0) |
| Number of prior systemic therapies: median | 0 |
| Performance status: ECOG | |
| 0: 11 (27.5%) | |
| 1: 29 (72.5%) | |
| 2: 0 | |
| 3: 0 | |
| 4: 0 | |
| Patient Characteristics | |
|---|---|
| Number of patients | |
| Male | 25 (62.5%) |
| Female | 15 (37.5%) |
| Stage | |
| 1 | 3 (7.5%) |
| 2 | 9 (22.5%) |
| 3 | 10 (25.0%) |
| 4 | 18 (45.0%) |
| Age (years), median (range) | 55.0 (47.8-61.0) |
| Number of prior systemic therapies: median | 0 |
| Performance status: ECOG | |
| 0: 11 (27.5%) | |
| 1: 29 (72.5%) | |
| 2: 0 | |
| 3: 0 | |
| 4: 0 | |
| Patient Characteristics | |
|---|---|
| Number of patients | |
| Male | 25 (62.5%) |
| Female | 15 (37.5%) |
| Stage | |
| 1 | 3 (7.5%) |
| 2 | 9 (22.5%) |
| 3 | 10 (25.0%) |
| 4 | 18 (45.0%) |
| Age (years), median (range) | 55.0 (47.8-61.0) |
| Number of prior systemic therapies: median | 0 |
| Performance status: ECOG | |
| 0: 11 (27.5%) | |
| 1: 29 (72.5%) | |
| 2: 0 | |
| 3: 0 | |
| 4: 0 | |
| Cancer types or histologic subtypes | Number |
|---|---|
| Peripheral T-cell lymphoma-not otherwise specified | 19 (47.5%) |
| Angioimmunoblastic T-cell lymphoma | 9 (22.5%) |
| ALK-positive anaplastic large-cell lymphoma | 6 (15.0%) |
| ALK-negative anaplastic large-cell lymphoma | 5 (12.5%) |
| Subcutaneous panniculitis-like T-cell lymphoma with systemic involvement | 1 (2.5%) |
| Cancer types or histologic subtypes | Number |
|---|---|
| Peripheral T-cell lymphoma-not otherwise specified | 19 (47.5%) |
| Angioimmunoblastic T-cell lymphoma | 9 (22.5%) |
| ALK-positive anaplastic large-cell lymphoma | 6 (15.0%) |
| ALK-negative anaplastic large-cell lymphoma | 5 (12.5%) |
| Subcutaneous panniculitis-like T-cell lymphoma with systemic involvement | 1 (2.5%) |
| Cancer types or histologic subtypes | Number |
|---|---|
| Peripheral T-cell lymphoma-not otherwise specified | 19 (47.5%) |
| Angioimmunoblastic T-cell lymphoma | 9 (22.5%) |
| ALK-positive anaplastic large-cell lymphoma | 6 (15.0%) |
| ALK-negative anaplastic large-cell lymphoma | 5 (12.5%) |
| Subcutaneous panniculitis-like T-cell lymphoma with systemic involvement | 1 (2.5%) |
| Cancer types or histologic subtypes | Number |
|---|---|
| Peripheral T-cell lymphoma-not otherwise specified | 19 (47.5%) |
| Angioimmunoblastic T-cell lymphoma | 9 (22.5%) |
| ALK-positive anaplastic large-cell lymphoma | 6 (15.0%) |
| ALK-negative anaplastic large-cell lymphoma | 5 (12.5%) |
| Subcutaneous panniculitis-like T-cell lymphoma with systemic involvement | 1 (2.5%) |
| Primary Assessment Method | |
|---|---|
| Number of patients screened | 42 |
| Number of patients enrolled | 41 |
| Number of patients evaluable for toxicity | 40 |
| Number of patients evaluated for efficacy | 40 |
| Evaluation method | Other (standardize response criteria for non-Hodgkin’s lymphomas: International Working Group) |
| Response assessment | |
| CR | 25 (62.5%) |
| PR | 8 (20.0%) |
| SD | 2 (5.0%) |
| PD | 4 (10.0%) |
| Not evaluable | 1 (2.5%) |
| Median duration assessment | |
| PFS | 2-year PFS rate: 55.1% (95% CI: 40.5-74.9) 5-year PFS rate: 52.0% (95% CI: 37.5-72.2) 8-year PFS rate: 52.0% (95% CI: 37.5-72.2) |
| OS | 2-year OS rate: 80.0% (95% CI: 68.5-93.4) 5-year OS rate: 62.5% (95% CI: 49.2-79.5) 8-year OS rate: 54.3% (95% CI: 40.7-72.5) |
| Response duration | 2-year DoR rate: 58.7% (95% CI: 44.6-77.2) 5-year DoR rate: 55.8% (95% CI: 41.6-74.7) 8-year DoR rate: 55.8% (95% CI: 41.6-74.7) |
| Outcomes notes | See Figures 2 and 3. See also Table 1 and Table 2. Treatment-related AEs are described in Table 3. As AEs of special interest related to PLD, mucositis and hand-foot syndrome of any grade were reported in 37.5% (15/40) and 17.5% (7/40) of patients, respectively. Treatment-related AEs leading to treatment discontinuation included pneumonitis (n = 3) and CTRCD (n = 2). No death associated with the combination regimen was observed |
| Primary Assessment Method | |
|---|---|
| Number of patients screened | 42 |
| Number of patients enrolled | 41 |
| Number of patients evaluable for toxicity | 40 |
| Number of patients evaluated for efficacy | 40 |
| Evaluation method | Other (standardize response criteria for non-Hodgkin’s lymphomas: International Working Group) |
| Response assessment | |
| CR | 25 (62.5%) |
| PR | 8 (20.0%) |
| SD | 2 (5.0%) |
| PD | 4 (10.0%) |
| Not evaluable | 1 (2.5%) |
| Median duration assessment | |
| PFS | 2-year PFS rate: 55.1% (95% CI: 40.5-74.9) 5-year PFS rate: 52.0% (95% CI: 37.5-72.2) 8-year PFS rate: 52.0% (95% CI: 37.5-72.2) |
| OS | 2-year OS rate: 80.0% (95% CI: 68.5-93.4) 5-year OS rate: 62.5% (95% CI: 49.2-79.5) 8-year OS rate: 54.3% (95% CI: 40.7-72.5) |
| Response duration | 2-year DoR rate: 58.7% (95% CI: 44.6-77.2) 5-year DoR rate: 55.8% (95% CI: 41.6-74.7) 8-year DoR rate: 55.8% (95% CI: 41.6-74.7) |
| Outcomes notes | See Figures 2 and 3. See also Table 1 and Table 2. Treatment-related AEs are described in Table 3. As AEs of special interest related to PLD, mucositis and hand-foot syndrome of any grade were reported in 37.5% (15/40) and 17.5% (7/40) of patients, respectively. Treatment-related AEs leading to treatment discontinuation included pneumonitis (n = 3) and CTRCD (n = 2). No death associated with the combination regimen was observed |
| Primary Assessment Method | |
|---|---|
| Number of patients screened | 42 |
| Number of patients enrolled | 41 |
| Number of patients evaluable for toxicity | 40 |
| Number of patients evaluated for efficacy | 40 |
| Evaluation method | Other (standardize response criteria for non-Hodgkin’s lymphomas: International Working Group) |
| Response assessment | |
| CR | 25 (62.5%) |
| PR | 8 (20.0%) |
| SD | 2 (5.0%) |
| PD | 4 (10.0%) |
| Not evaluable | 1 (2.5%) |
| Median duration assessment | |
| PFS | 2-year PFS rate: 55.1% (95% CI: 40.5-74.9) 5-year PFS rate: 52.0% (95% CI: 37.5-72.2) 8-year PFS rate: 52.0% (95% CI: 37.5-72.2) |
| OS | 2-year OS rate: 80.0% (95% CI: 68.5-93.4) 5-year OS rate: 62.5% (95% CI: 49.2-79.5) 8-year OS rate: 54.3% (95% CI: 40.7-72.5) |
| Response duration | 2-year DoR rate: 58.7% (95% CI: 44.6-77.2) 5-year DoR rate: 55.8% (95% CI: 41.6-74.7) 8-year DoR rate: 55.8% (95% CI: 41.6-74.7) |
| Outcomes notes | See Figures 2 and 3. See also Table 1 and Table 2. Treatment-related AEs are described in Table 3. As AEs of special interest related to PLD, mucositis and hand-foot syndrome of any grade were reported in 37.5% (15/40) and 17.5% (7/40) of patients, respectively. Treatment-related AEs leading to treatment discontinuation included pneumonitis (n = 3) and CTRCD (n = 2). No death associated with the combination regimen was observed |
| Primary Assessment Method | |
|---|---|
| Number of patients screened | 42 |
| Number of patients enrolled | 41 |
| Number of patients evaluable for toxicity | 40 |
| Number of patients evaluated for efficacy | 40 |
| Evaluation method | Other (standardize response criteria for non-Hodgkin’s lymphomas: International Working Group) |
| Response assessment | |
| CR | 25 (62.5%) |
| PR | 8 (20.0%) |
| SD | 2 (5.0%) |
| PD | 4 (10.0%) |
| Not evaluable | 1 (2.5%) |
| Median duration assessment | |
| PFS | 2-year PFS rate: 55.1% (95% CI: 40.5-74.9) 5-year PFS rate: 52.0% (95% CI: 37.5-72.2) 8-year PFS rate: 52.0% (95% CI: 37.5-72.2) |
| OS | 2-year OS rate: 80.0% (95% CI: 68.5-93.4) 5-year OS rate: 62.5% (95% CI: 49.2-79.5) 8-year OS rate: 54.3% (95% CI: 40.7-72.5) |
| Response duration | 2-year DoR rate: 58.7% (95% CI: 44.6-77.2) 5-year DoR rate: 55.8% (95% CI: 41.6-74.7) 8-year DoR rate: 55.8% (95% CI: 41.6-74.7) |
| Outcomes notes | See Figures 2 and 3. See also Table 1 and Table 2. Treatment-related AEs are described in Table 3. As AEs of special interest related to PLD, mucositis and hand-foot syndrome of any grade were reported in 37.5% (15/40) and 17.5% (7/40) of patients, respectively. Treatment-related AEs leading to treatment discontinuation included pneumonitis (n = 3) and CTRCD (n = 2). No death associated with the combination regimen was observed |
Assessment, Analysis, and Discussion
| Completion | Study completed |
|---|---|
| Investigator’s assessment | Active but results overtaken by other developments |
| Completion | Study completed |
|---|---|
| Investigator’s assessment | Active but results overtaken by other developments |
| Completion | Study completed |
|---|---|
| Investigator’s assessment | Active but results overtaken by other developments |
| Completion | Study completed |
|---|---|
| Investigator’s assessment | Active but results overtaken by other developments |
Currently, attempts to improve the efficacy of CHOP have been largely unsuccessful, being primarily carried out in single-arm or phase 2 studies.6-9 Despite the observed OS benefit of brentuximab vedotin (BV) plus CHP for CD30-positive PTCL in the ECHELON-2 study,10,11 clinical benefit population was primarily patients with ALCL. So far, the CHOP or a CHOP-like regimen remains the preferred first-line therapy option in PTCL irrespective of biomarker status. To our knowledge, this study represented the first and prospective long-term results for up to 8 years of PLD-containing regimen in patients with newly diagnosed aggressive PTCL. This study yielded an encouraging ORR (82.5%) at the EOT to 6 cycles of the combination regimen, as well as offered long-term survival benefits in this population, with an 8-year PFS rate of 52.0% and an 8-year OS rate of 54.3%. Meanwhile, this combination had a manageable tolerability, particularly with less cardiotoxicity. Based on these impressive long-term results, the combination regimen may serve as a reasonable first-line approach with a favorable benefit-risk balance in treating this disease.
Kaplan-Meier curves of overall survival according to progression of disease within 24 months (POD24) status. Median OS was longer in non-POD24 patients than in POD24 patients (not reached vs 41.2 months; P < .001).
The changes of left ventricular ejection fraction (LVEF) over time from baseline to the end of treatment in 39 with post-treatment LVEF results. From baseline to the end of treatment, 30 patients exhibited different degrees of LVEF decline, with a mean LVEF decline of 7.2% (range, 1.0%-19.0%; SD, 4.3%). The LVEF decline of ≥10% was observed in 6 patients (15.0%), of which 2 (5.0%) patients had a resting LVEF of <50%. Thirteen (43.3%) of 30 patients displayed a subsequent recovery of LVEF.
Patient and disease characteristics.
| Characteristics | Total (n = 40) |
|---|---|
| Age (years), median (IQR) | 55.0 (47.8-61.0) |
| Age (years), n (%), ≤60/>60 | 28 (70.0)/12 (30.0) |
| Gender, n (%), male/female | 25 (62.5)/15 (37.5) |
| ECOG performance status, n (%), 0/1 | 11 (27.5)/29 (72.5) |
| Disease stage, n (%) | |
| 1 | 3 (7.5) |
| 2 | 9 (22.5) |
| 3 | 10 (25.0) |
| 4 | 18 (45.0) |
| Histologic subtypes | |
| PTCL-NOS | 19 (47.5) |
| AITL | 9 (22.5) |
| ALK-positive ALCL | 6 (15.0) |
| ALK-negative ALCL | 5 (12.5) |
| SPTL with systemic involvement | 1 (2.5) |
| B symptoms present, n (%) | 10 (25.0) |
| Increased serum LDH, n (%) | 12 (30.0) |
| Extranodal sites > 1, n (%) | 6 (15.0) |
| Bone marrow involvement, n (%) | 1 (2.5) |
| Bulky disease ≥ 7.5cm, n (%) | 2 (5.0) |
| Decreased albumin, n (%) | 12 (30.0) |
| Increased serum β2 microglobulin, n (%) | 13 (34.2) |
| IPI score, n (%) | |
| 0-1 | 19 (47.5) |
| 2 | 18 (45.0) |
| 3 | 3 (7.5) |
| PIT score, n (%) | |
| 0 | 16 (40.0) |
| 1 | 23 (57.5) |
| 2 | 1 (2.5) |
| Modified PIT score, n (%), 0-1/2 | 32 (80.0)/8 (20.0) |
| Characteristics | Total (n = 40) |
|---|---|
| Age (years), median (IQR) | 55.0 (47.8-61.0) |
| Age (years), n (%), ≤60/>60 | 28 (70.0)/12 (30.0) |
| Gender, n (%), male/female | 25 (62.5)/15 (37.5) |
| ECOG performance status, n (%), 0/1 | 11 (27.5)/29 (72.5) |
| Disease stage, n (%) | |
| 1 | 3 (7.5) |
| 2 | 9 (22.5) |
| 3 | 10 (25.0) |
| 4 | 18 (45.0) |
| Histologic subtypes | |
| PTCL-NOS | 19 (47.5) |
| AITL | 9 (22.5) |
| ALK-positive ALCL | 6 (15.0) |
| ALK-negative ALCL | 5 (12.5) |
| SPTL with systemic involvement | 1 (2.5) |
| B symptoms present, n (%) | 10 (25.0) |
| Increased serum LDH, n (%) | 12 (30.0) |
| Extranodal sites > 1, n (%) | 6 (15.0) |
| Bone marrow involvement, n (%) | 1 (2.5) |
| Bulky disease ≥ 7.5cm, n (%) | 2 (5.0) |
| Decreased albumin, n (%) | 12 (30.0) |
| Increased serum β2 microglobulin, n (%) | 13 (34.2) |
| IPI score, n (%) | |
| 0-1 | 19 (47.5) |
| 2 | 18 (45.0) |
| 3 | 3 (7.5) |
| PIT score, n (%) | |
| 0 | 16 (40.0) |
| 1 | 23 (57.5) |
| 2 | 1 (2.5) |
| Modified PIT score, n (%), 0-1/2 | 32 (80.0)/8 (20.0) |
Abbreviations: PTCL-NOS, peripheral T-cell lymphoma-not otherwise specified; AITL, angioimmunoblastic T-cell lymphoma; ALK, anaplastic lymphoma kinase; ALCL, anaplastic large cell lymphoma; SPTL, subcutaneous panniculitis-like T-cell lymphoma; IQR, interquartile range; LDH, lactate dehydrogenase; IPI, International Prognostic Index; ECOG, Eastern Cooperative Oncology Group; PIT, Prognostic Index for T-cell lymphoma.
Patient and disease characteristics.
| Characteristics | Total (n = 40) |
|---|---|
| Age (years), median (IQR) | 55.0 (47.8-61.0) |
| Age (years), n (%), ≤60/>60 | 28 (70.0)/12 (30.0) |
| Gender, n (%), male/female | 25 (62.5)/15 (37.5) |
| ECOG performance status, n (%), 0/1 | 11 (27.5)/29 (72.5) |
| Disease stage, n (%) | |
| 1 | 3 (7.5) |
| 2 | 9 (22.5) |
| 3 | 10 (25.0) |
| 4 | 18 (45.0) |
| Histologic subtypes | |
| PTCL-NOS | 19 (47.5) |
| AITL | 9 (22.5) |
| ALK-positive ALCL | 6 (15.0) |
| ALK-negative ALCL | 5 (12.5) |
| SPTL with systemic involvement | 1 (2.5) |
| B symptoms present, n (%) | 10 (25.0) |
| Increased serum LDH, n (%) | 12 (30.0) |
| Extranodal sites > 1, n (%) | 6 (15.0) |
| Bone marrow involvement, n (%) | 1 (2.5) |
| Bulky disease ≥ 7.5cm, n (%) | 2 (5.0) |
| Decreased albumin, n (%) | 12 (30.0) |
| Increased serum β2 microglobulin, n (%) | 13 (34.2) |
| IPI score, n (%) | |
| 0-1 | 19 (47.5) |
| 2 | 18 (45.0) |
| 3 | 3 (7.5) |
| PIT score, n (%) | |
| 0 | 16 (40.0) |
| 1 | 23 (57.5) |
| 2 | 1 (2.5) |
| Modified PIT score, n (%), 0-1/2 | 32 (80.0)/8 (20.0) |
| Characteristics | Total (n = 40) |
|---|---|
| Age (years), median (IQR) | 55.0 (47.8-61.0) |
| Age (years), n (%), ≤60/>60 | 28 (70.0)/12 (30.0) |
| Gender, n (%), male/female | 25 (62.5)/15 (37.5) |
| ECOG performance status, n (%), 0/1 | 11 (27.5)/29 (72.5) |
| Disease stage, n (%) | |
| 1 | 3 (7.5) |
| 2 | 9 (22.5) |
| 3 | 10 (25.0) |
| 4 | 18 (45.0) |
| Histologic subtypes | |
| PTCL-NOS | 19 (47.5) |
| AITL | 9 (22.5) |
| ALK-positive ALCL | 6 (15.0) |
| ALK-negative ALCL | 5 (12.5) |
| SPTL with systemic involvement | 1 (2.5) |
| B symptoms present, n (%) | 10 (25.0) |
| Increased serum LDH, n (%) | 12 (30.0) |
| Extranodal sites > 1, n (%) | 6 (15.0) |
| Bone marrow involvement, n (%) | 1 (2.5) |
| Bulky disease ≥ 7.5cm, n (%) | 2 (5.0) |
| Decreased albumin, n (%) | 12 (30.0) |
| Increased serum β2 microglobulin, n (%) | 13 (34.2) |
| IPI score, n (%) | |
| 0-1 | 19 (47.5) |
| 2 | 18 (45.0) |
| 3 | 3 (7.5) |
| PIT score, n (%) | |
| 0 | 16 (40.0) |
| 1 | 23 (57.5) |
| 2 | 1 (2.5) |
| Modified PIT score, n (%), 0-1/2 | 32 (80.0)/8 (20.0) |
Abbreviations: PTCL-NOS, peripheral T-cell lymphoma-not otherwise specified; AITL, angioimmunoblastic T-cell lymphoma; ALK, anaplastic lymphoma kinase; ALCL, anaplastic large cell lymphoma; SPTL, subcutaneous panniculitis-like T-cell lymphoma; IQR, interquartile range; LDH, lactate dehydrogenase; IPI, International Prognostic Index; ECOG, Eastern Cooperative Oncology Group; PIT, Prognostic Index for T-cell lymphoma.
Tumor response at the EOT and survival outcomes by histologic subtypes.
| Total (n = 40) | PTCL-NOS (n = 19) | AITL (n = 9) | ALK-positive ALCL (n = 6) | ALK-negative ALCL (n = 5) | SPTL with systemic involvement (n = 1) | |
|---|---|---|---|---|---|---|
| Tumor responses at EOT, n (%) | ||||||
| CR | 25 (62.5) | 9 (47.4) | 7 (77.8) | 4 (66.7) | 4 (80.0) | 1 (100.0) |
| PR | 8 (20.0) | 4 (21.0) | 2 (22.2) | 1 (16.7) | 1 (20.0) | 0 |
| SD | 2 (5.0) | 2 (10.5) | 0 | 0 | 0 | 0 |
| PD | 4 (10.0) | 3 (15.8) | 0 | 1 (16.7) | 0 | 0 |
| NE | 1 (2.5) | 1 (5.3) | 0 | 0 | 0 | 0 |
| ORR at EOT, n (%, 95% CI) | 33 (82.5, 67.2-92.7) | 13 (68.4, 43.4-87.4) | 9 (100.0, 66.4-100.9) | 5 (83.3, 35.9-99.6) | 5 (100.0, 47.8-100.0) | 1 (100.0, 2.5-100.0) |
| Median PFS (months, 95% CI) | NR | 22.0 (11.0-NE) | 58.6 (9.9-NE) | NR | 10.5 (7.4-NE) | NE |
| 2-year PFS (%, 95% CI) | 55.1 (40.5-74.9) | 48.1 (27.4-84.5) | 62.5 (36.5-100.0) | 66.7 (37.9-100.0) | 40.0 (13.7-100.0) | 100.0 (100.0-100.0) |
| 5-year PFS (%, 95% CI) | 52.0 (37.5-72.2) | 48.1 (27.4-84.5) | 50.0 (25.0-100.0) | 66.7 (37.9-100.0) | 40.0 (13.7-100.0) | 100.0 (100.0-100.0) |
| 8-year PFS (%, 95% CI) | 52.0 (37.5-72.2) | 48.1 (27.4-84.5) | 50.0 (25.0-100.0) | 66.7 (37.9-100.0) | 40.0 (13.7-100.0) | 100.0 (100.0-100.0) |
| Median OS (months, 95% CI) | NR | NR | 65.2 (42.7-NE) | NR | NR | NE |
| 2-year OS (%, 95% CI) | 80.0 (68.5-93.4) | 73.7 (56.3-96.4) | 88.9 (70.6-100.0) | 83.3 (58.3-100.0) | 80.0 (51.6-100.0) | 100.0 (100.0-100.0) |
| 5-year OS (%, 95% CI) | 62.5 (49.2-79.5) | 57.9 (39.5-85.0) | 55.6 (31.0-99.7) | 66.7 (37.9-100.0) | 80.0 (51.6-100.0) | 100.0 (100.0-100.0) |
| 8-year OS (%, 95% CI) | 54.3 (40.7-72.5) | 52.1 (33.7-80.5) | 44.4 (21.4-92.3) | 66.7 (37.9-100.0) | 60.0 (29.3-100.0) | 100.0 (100.0-100.0) |
| Median DoR (months, 95% CI) | NR | NR | NR | NR | 9.0 (6.1-NE) | NE |
| 2-year DoR (%, 95% CI) | 58.7 (44.6-77.2) | 55.0 (35.0-86.5) | 64.8 (39.3-100.0) | 66.7 (37.9-100.0) | 40.0 (13.7-100.0) | 100.0 (100.0-100.0) |
| 5-year DoR (%, 95% CI) | 55.8 (41.6-74.7) | 55.0 (35.0-86.5) | 51.9 (26.7-100.0) | 66.7 (37.9-100.0) | 40.0 (13.7-100.0) | 100.0 (100.0-100.0) |
| 8-year DoR (%, 95% CI) | 55.8 (41.6-74.7) | 55.0 (35.0-86.5) | 51.9 (26.7-100.0) | 66.7 (37.9-100.0) | 40.0 (13.7-100.0) | 100.0 (100.0-100.0) |
| Total (n = 40) | PTCL-NOS (n = 19) | AITL (n = 9) | ALK-positive ALCL (n = 6) | ALK-negative ALCL (n = 5) | SPTL with systemic involvement (n = 1) | |
|---|---|---|---|---|---|---|
| Tumor responses at EOT, n (%) | ||||||
| CR | 25 (62.5) | 9 (47.4) | 7 (77.8) | 4 (66.7) | 4 (80.0) | 1 (100.0) |
| PR | 8 (20.0) | 4 (21.0) | 2 (22.2) | 1 (16.7) | 1 (20.0) | 0 |
| SD | 2 (5.0) | 2 (10.5) | 0 | 0 | 0 | 0 |
| PD | 4 (10.0) | 3 (15.8) | 0 | 1 (16.7) | 0 | 0 |
| NE | 1 (2.5) | 1 (5.3) | 0 | 0 | 0 | 0 |
| ORR at EOT, n (%, 95% CI) | 33 (82.5, 67.2-92.7) | 13 (68.4, 43.4-87.4) | 9 (100.0, 66.4-100.9) | 5 (83.3, 35.9-99.6) | 5 (100.0, 47.8-100.0) | 1 (100.0, 2.5-100.0) |
| Median PFS (months, 95% CI) | NR | 22.0 (11.0-NE) | 58.6 (9.9-NE) | NR | 10.5 (7.4-NE) | NE |
| 2-year PFS (%, 95% CI) | 55.1 (40.5-74.9) | 48.1 (27.4-84.5) | 62.5 (36.5-100.0) | 66.7 (37.9-100.0) | 40.0 (13.7-100.0) | 100.0 (100.0-100.0) |
| 5-year PFS (%, 95% CI) | 52.0 (37.5-72.2) | 48.1 (27.4-84.5) | 50.0 (25.0-100.0) | 66.7 (37.9-100.0) | 40.0 (13.7-100.0) | 100.0 (100.0-100.0) |
| 8-year PFS (%, 95% CI) | 52.0 (37.5-72.2) | 48.1 (27.4-84.5) | 50.0 (25.0-100.0) | 66.7 (37.9-100.0) | 40.0 (13.7-100.0) | 100.0 (100.0-100.0) |
| Median OS (months, 95% CI) | NR | NR | 65.2 (42.7-NE) | NR | NR | NE |
| 2-year OS (%, 95% CI) | 80.0 (68.5-93.4) | 73.7 (56.3-96.4) | 88.9 (70.6-100.0) | 83.3 (58.3-100.0) | 80.0 (51.6-100.0) | 100.0 (100.0-100.0) |
| 5-year OS (%, 95% CI) | 62.5 (49.2-79.5) | 57.9 (39.5-85.0) | 55.6 (31.0-99.7) | 66.7 (37.9-100.0) | 80.0 (51.6-100.0) | 100.0 (100.0-100.0) |
| 8-year OS (%, 95% CI) | 54.3 (40.7-72.5) | 52.1 (33.7-80.5) | 44.4 (21.4-92.3) | 66.7 (37.9-100.0) | 60.0 (29.3-100.0) | 100.0 (100.0-100.0) |
| Median DoR (months, 95% CI) | NR | NR | NR | NR | 9.0 (6.1-NE) | NE |
| 2-year DoR (%, 95% CI) | 58.7 (44.6-77.2) | 55.0 (35.0-86.5) | 64.8 (39.3-100.0) | 66.7 (37.9-100.0) | 40.0 (13.7-100.0) | 100.0 (100.0-100.0) |
| 5-year DoR (%, 95% CI) | 55.8 (41.6-74.7) | 55.0 (35.0-86.5) | 51.9 (26.7-100.0) | 66.7 (37.9-100.0) | 40.0 (13.7-100.0) | 100.0 (100.0-100.0) |
| 8-year DoR (%, 95% CI) | 55.8 (41.6-74.7) | 55.0 (35.0-86.5) | 51.9 (26.7-100.0) | 66.7 (37.9-100.0) | 40.0 (13.7-100.0) | 100.0 (100.0-100.0) |
Abbreviations: PTCL-NOS, peripheral T-cell lymphoma-not otherwise specified; AITL, angioimmunoblastic T-cell lymphoma; ALK, anaplastic lymphoma kinase; ALCL, anaplastic large cell lymphoma; SPTL, subcutaneous panniculitis-like T-cell lymphoma; EOT, end of treatment; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NE, not evaluable; ORR, objective response rate; PFS, progression-free survival; NR, not reached; OS, overall survival; DoR, duration of response.
Tumor response at the EOT and survival outcomes by histologic subtypes.
| Total (n = 40) | PTCL-NOS (n = 19) | AITL (n = 9) | ALK-positive ALCL (n = 6) | ALK-negative ALCL (n = 5) | SPTL with systemic involvement (n = 1) | |
|---|---|---|---|---|---|---|
| Tumor responses at EOT, n (%) | ||||||
| CR | 25 (62.5) | 9 (47.4) | 7 (77.8) | 4 (66.7) | 4 (80.0) | 1 (100.0) |
| PR | 8 (20.0) | 4 (21.0) | 2 (22.2) | 1 (16.7) | 1 (20.0) | 0 |
| SD | 2 (5.0) | 2 (10.5) | 0 | 0 | 0 | 0 |
| PD | 4 (10.0) | 3 (15.8) | 0 | 1 (16.7) | 0 | 0 |
| NE | 1 (2.5) | 1 (5.3) | 0 | 0 | 0 | 0 |
| ORR at EOT, n (%, 95% CI) | 33 (82.5, 67.2-92.7) | 13 (68.4, 43.4-87.4) | 9 (100.0, 66.4-100.9) | 5 (83.3, 35.9-99.6) | 5 (100.0, 47.8-100.0) | 1 (100.0, 2.5-100.0) |
| Median PFS (months, 95% CI) | NR | 22.0 (11.0-NE) | 58.6 (9.9-NE) | NR | 10.5 (7.4-NE) | NE |
| 2-year PFS (%, 95% CI) | 55.1 (40.5-74.9) | 48.1 (27.4-84.5) | 62.5 (36.5-100.0) | 66.7 (37.9-100.0) | 40.0 (13.7-100.0) | 100.0 (100.0-100.0) |
| 5-year PFS (%, 95% CI) | 52.0 (37.5-72.2) | 48.1 (27.4-84.5) | 50.0 (25.0-100.0) | 66.7 (37.9-100.0) | 40.0 (13.7-100.0) | 100.0 (100.0-100.0) |
| 8-year PFS (%, 95% CI) | 52.0 (37.5-72.2) | 48.1 (27.4-84.5) | 50.0 (25.0-100.0) | 66.7 (37.9-100.0) | 40.0 (13.7-100.0) | 100.0 (100.0-100.0) |
| Median OS (months, 95% CI) | NR | NR | 65.2 (42.7-NE) | NR | NR | NE |
| 2-year OS (%, 95% CI) | 80.0 (68.5-93.4) | 73.7 (56.3-96.4) | 88.9 (70.6-100.0) | 83.3 (58.3-100.0) | 80.0 (51.6-100.0) | 100.0 (100.0-100.0) |
| 5-year OS (%, 95% CI) | 62.5 (49.2-79.5) | 57.9 (39.5-85.0) | 55.6 (31.0-99.7) | 66.7 (37.9-100.0) | 80.0 (51.6-100.0) | 100.0 (100.0-100.0) |
| 8-year OS (%, 95% CI) | 54.3 (40.7-72.5) | 52.1 (33.7-80.5) | 44.4 (21.4-92.3) | 66.7 (37.9-100.0) | 60.0 (29.3-100.0) | 100.0 (100.0-100.0) |
| Median DoR (months, 95% CI) | NR | NR | NR | NR | 9.0 (6.1-NE) | NE |
| 2-year DoR (%, 95% CI) | 58.7 (44.6-77.2) | 55.0 (35.0-86.5) | 64.8 (39.3-100.0) | 66.7 (37.9-100.0) | 40.0 (13.7-100.0) | 100.0 (100.0-100.0) |
| 5-year DoR (%, 95% CI) | 55.8 (41.6-74.7) | 55.0 (35.0-86.5) | 51.9 (26.7-100.0) | 66.7 (37.9-100.0) | 40.0 (13.7-100.0) | 100.0 (100.0-100.0) |
| 8-year DoR (%, 95% CI) | 55.8 (41.6-74.7) | 55.0 (35.0-86.5) | 51.9 (26.7-100.0) | 66.7 (37.9-100.0) | 40.0 (13.7-100.0) | 100.0 (100.0-100.0) |
| Total (n = 40) | PTCL-NOS (n = 19) | AITL (n = 9) | ALK-positive ALCL (n = 6) | ALK-negative ALCL (n = 5) | SPTL with systemic involvement (n = 1) | |
|---|---|---|---|---|---|---|
| Tumor responses at EOT, n (%) | ||||||
| CR | 25 (62.5) | 9 (47.4) | 7 (77.8) | 4 (66.7) | 4 (80.0) | 1 (100.0) |
| PR | 8 (20.0) | 4 (21.0) | 2 (22.2) | 1 (16.7) | 1 (20.0) | 0 |
| SD | 2 (5.0) | 2 (10.5) | 0 | 0 | 0 | 0 |
| PD | 4 (10.0) | 3 (15.8) | 0 | 1 (16.7) | 0 | 0 |
| NE | 1 (2.5) | 1 (5.3) | 0 | 0 | 0 | 0 |
| ORR at EOT, n (%, 95% CI) | 33 (82.5, 67.2-92.7) | 13 (68.4, 43.4-87.4) | 9 (100.0, 66.4-100.9) | 5 (83.3, 35.9-99.6) | 5 (100.0, 47.8-100.0) | 1 (100.0, 2.5-100.0) |
| Median PFS (months, 95% CI) | NR | 22.0 (11.0-NE) | 58.6 (9.9-NE) | NR | 10.5 (7.4-NE) | NE |
| 2-year PFS (%, 95% CI) | 55.1 (40.5-74.9) | 48.1 (27.4-84.5) | 62.5 (36.5-100.0) | 66.7 (37.9-100.0) | 40.0 (13.7-100.0) | 100.0 (100.0-100.0) |
| 5-year PFS (%, 95% CI) | 52.0 (37.5-72.2) | 48.1 (27.4-84.5) | 50.0 (25.0-100.0) | 66.7 (37.9-100.0) | 40.0 (13.7-100.0) | 100.0 (100.0-100.0) |
| 8-year PFS (%, 95% CI) | 52.0 (37.5-72.2) | 48.1 (27.4-84.5) | 50.0 (25.0-100.0) | 66.7 (37.9-100.0) | 40.0 (13.7-100.0) | 100.0 (100.0-100.0) |
| Median OS (months, 95% CI) | NR | NR | 65.2 (42.7-NE) | NR | NR | NE |
| 2-year OS (%, 95% CI) | 80.0 (68.5-93.4) | 73.7 (56.3-96.4) | 88.9 (70.6-100.0) | 83.3 (58.3-100.0) | 80.0 (51.6-100.0) | 100.0 (100.0-100.0) |
| 5-year OS (%, 95% CI) | 62.5 (49.2-79.5) | 57.9 (39.5-85.0) | 55.6 (31.0-99.7) | 66.7 (37.9-100.0) | 80.0 (51.6-100.0) | 100.0 (100.0-100.0) |
| 8-year OS (%, 95% CI) | 54.3 (40.7-72.5) | 52.1 (33.7-80.5) | 44.4 (21.4-92.3) | 66.7 (37.9-100.0) | 60.0 (29.3-100.0) | 100.0 (100.0-100.0) |
| Median DoR (months, 95% CI) | NR | NR | NR | NR | 9.0 (6.1-NE) | NE |
| 2-year DoR (%, 95% CI) | 58.7 (44.6-77.2) | 55.0 (35.0-86.5) | 64.8 (39.3-100.0) | 66.7 (37.9-100.0) | 40.0 (13.7-100.0) | 100.0 (100.0-100.0) |
| 5-year DoR (%, 95% CI) | 55.8 (41.6-74.7) | 55.0 (35.0-86.5) | 51.9 (26.7-100.0) | 66.7 (37.9-100.0) | 40.0 (13.7-100.0) | 100.0 (100.0-100.0) |
| 8-year DoR (%, 95% CI) | 55.8 (41.6-74.7) | 55.0 (35.0-86.5) | 51.9 (26.7-100.0) | 66.7 (37.9-100.0) | 40.0 (13.7-100.0) | 100.0 (100.0-100.0) |
Abbreviations: PTCL-NOS, peripheral T-cell lymphoma-not otherwise specified; AITL, angioimmunoblastic T-cell lymphoma; ALK, anaplastic lymphoma kinase; ALCL, anaplastic large cell lymphoma; SPTL, subcutaneous panniculitis-like T-cell lymphoma; EOT, end of treatment; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NE, not evaluable; ORR, objective response rate; PFS, progression-free survival; NR, not reached; OS, overall survival; DoR, duration of response.
Treatment-related adverse events in all patients (n = 40).
| Adverse events | Any grade | Grade 1-2 | Grade 3-4 |
|---|---|---|---|
| Total, n (%) | 40 (100.0) | 4 (10.0) | 36 (90.0) |
| Hematological toxicity, n (%) | |||
| Leukopenia | 40 (100.0) | 8 (20.0) | 32 (80.0) |
| Neutropenia | 39 (97.5) | 4 (10.0) | 35 (87.5) |
| Anemia | 39 (97.5) | 32 (80.0) | 7 (17.5) |
| Thrombocytopenia | 15 (37.5) | 13 (32.5) | 2 (5.0) |
| Febrile neutropenia | 2 (5.0) | 0 | 2 (5.0) |
| Non-hematological toxicity, n (%) | |||
| Alopecia | 28 (70.0) | 28 (70.0) | 0 |
| Hypoalbuminemia | 21 (52.5) | 21 (52.5) | 0 |
| Pneumonitis | 21 (52.5) | 14 (35.0) | 7 (17.5) |
| ALT increased | 21 (52.5) | 19 (47.5) | 2 (5.0) |
| AST increased | 19 (47.5) | 19 (47.5) | 0 |
| Pyrexia | 19 (47.5) | 19 (47.5) | 0 |
| Mucositis | 15 (37.5) | 11 (27.5) | 4 (10.0) |
| GGT increased | 14 (35.0) | 14 (35.0) | 0 |
| Hyperglycemia | 12 (30.0) | 12 (30.0) | 0 |
| Fatigue | 11 (27.5) | 11 (27.5) | 0 |
| Cough | 11 (27.5) | 11 (27.5) | 0 |
| Hyperbilirubinemia | 8 (20.0) | 7 (17.5) | 1 (2.5) |
| Hand-foot syndrome | 7 (17.5) | 6 (15.0) | 1 (2.5) |
| Anorexia | 7 (17.5) | 7 (17.5) | 0 |
| Nausea | 6 (15.0) | 6 (15.0) | 0 |
| Hyperuricemia | 5 (12.5) | 5 (12.5) | 0 |
| Diarrhea | 5 (12.5) | 5 (12.5) | 0 |
| Constipation | 4 (10.0) | 4 (10.0) | 0 |
| Rash | 4 (10.0) | 4 (10.0) | 0 |
| Vomiting | 3 (7.5) | 3 (7.5) | 0 |
| Abdominal distension | 3 (7.5) | 3 (7.5) | 0 |
| Creatinine increased | 3 (7.5) | 3 (7.5) | 0 |
| Allergic reaction | 3 (7.5) | 3 (7.5) | 0 |
| Upper respiratory infection | 3 (7.5) | 3 (7.5) | 0 |
| Skin hyperpigmentation | 2 (5.0) | 2 (5.0) | 0 |
| Skin infection | 2 (5.0) | 2 (5.0) | 0 |
| Edema limbs | 2 (5.0) | 1 (2.5) | 1 (2.5) |
| Bullous dermatitis | 1 (2.5) | 0 | 1 (2.5) |
| Adverse events | Any grade | Grade 1-2 | Grade 3-4 |
|---|---|---|---|
| Total, n (%) | 40 (100.0) | 4 (10.0) | 36 (90.0) |
| Hematological toxicity, n (%) | |||
| Leukopenia | 40 (100.0) | 8 (20.0) | 32 (80.0) |
| Neutropenia | 39 (97.5) | 4 (10.0) | 35 (87.5) |
| Anemia | 39 (97.5) | 32 (80.0) | 7 (17.5) |
| Thrombocytopenia | 15 (37.5) | 13 (32.5) | 2 (5.0) |
| Febrile neutropenia | 2 (5.0) | 0 | 2 (5.0) |
| Non-hematological toxicity, n (%) | |||
| Alopecia | 28 (70.0) | 28 (70.0) | 0 |
| Hypoalbuminemia | 21 (52.5) | 21 (52.5) | 0 |
| Pneumonitis | 21 (52.5) | 14 (35.0) | 7 (17.5) |
| ALT increased | 21 (52.5) | 19 (47.5) | 2 (5.0) |
| AST increased | 19 (47.5) | 19 (47.5) | 0 |
| Pyrexia | 19 (47.5) | 19 (47.5) | 0 |
| Mucositis | 15 (37.5) | 11 (27.5) | 4 (10.0) |
| GGT increased | 14 (35.0) | 14 (35.0) | 0 |
| Hyperglycemia | 12 (30.0) | 12 (30.0) | 0 |
| Fatigue | 11 (27.5) | 11 (27.5) | 0 |
| Cough | 11 (27.5) | 11 (27.5) | 0 |
| Hyperbilirubinemia | 8 (20.0) | 7 (17.5) | 1 (2.5) |
| Hand-foot syndrome | 7 (17.5) | 6 (15.0) | 1 (2.5) |
| Anorexia | 7 (17.5) | 7 (17.5) | 0 |
| Nausea | 6 (15.0) | 6 (15.0) | 0 |
| Hyperuricemia | 5 (12.5) | 5 (12.5) | 0 |
| Diarrhea | 5 (12.5) | 5 (12.5) | 0 |
| Constipation | 4 (10.0) | 4 (10.0) | 0 |
| Rash | 4 (10.0) | 4 (10.0) | 0 |
| Vomiting | 3 (7.5) | 3 (7.5) | 0 |
| Abdominal distension | 3 (7.5) | 3 (7.5) | 0 |
| Creatinine increased | 3 (7.5) | 3 (7.5) | 0 |
| Allergic reaction | 3 (7.5) | 3 (7.5) | 0 |
| Upper respiratory infection | 3 (7.5) | 3 (7.5) | 0 |
| Skin hyperpigmentation | 2 (5.0) | 2 (5.0) | 0 |
| Skin infection | 2 (5.0) | 2 (5.0) | 0 |
| Edema limbs | 2 (5.0) | 1 (2.5) | 1 (2.5) |
| Bullous dermatitis | 1 (2.5) | 0 | 1 (2.5) |
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transpeptidase.
Treatment-related adverse events in all patients (n = 40).
| Adverse events | Any grade | Grade 1-2 | Grade 3-4 |
|---|---|---|---|
| Total, n (%) | 40 (100.0) | 4 (10.0) | 36 (90.0) |
| Hematological toxicity, n (%) | |||
| Leukopenia | 40 (100.0) | 8 (20.0) | 32 (80.0) |
| Neutropenia | 39 (97.5) | 4 (10.0) | 35 (87.5) |
| Anemia | 39 (97.5) | 32 (80.0) | 7 (17.5) |
| Thrombocytopenia | 15 (37.5) | 13 (32.5) | 2 (5.0) |
| Febrile neutropenia | 2 (5.0) | 0 | 2 (5.0) |
| Non-hematological toxicity, n (%) | |||
| Alopecia | 28 (70.0) | 28 (70.0) | 0 |
| Hypoalbuminemia | 21 (52.5) | 21 (52.5) | 0 |
| Pneumonitis | 21 (52.5) | 14 (35.0) | 7 (17.5) |
| ALT increased | 21 (52.5) | 19 (47.5) | 2 (5.0) |
| AST increased | 19 (47.5) | 19 (47.5) | 0 |
| Pyrexia | 19 (47.5) | 19 (47.5) | 0 |
| Mucositis | 15 (37.5) | 11 (27.5) | 4 (10.0) |
| GGT increased | 14 (35.0) | 14 (35.0) | 0 |
| Hyperglycemia | 12 (30.0) | 12 (30.0) | 0 |
| Fatigue | 11 (27.5) | 11 (27.5) | 0 |
| Cough | 11 (27.5) | 11 (27.5) | 0 |
| Hyperbilirubinemia | 8 (20.0) | 7 (17.5) | 1 (2.5) |
| Hand-foot syndrome | 7 (17.5) | 6 (15.0) | 1 (2.5) |
| Anorexia | 7 (17.5) | 7 (17.5) | 0 |
| Nausea | 6 (15.0) | 6 (15.0) | 0 |
| Hyperuricemia | 5 (12.5) | 5 (12.5) | 0 |
| Diarrhea | 5 (12.5) | 5 (12.5) | 0 |
| Constipation | 4 (10.0) | 4 (10.0) | 0 |
| Rash | 4 (10.0) | 4 (10.0) | 0 |
| Vomiting | 3 (7.5) | 3 (7.5) | 0 |
| Abdominal distension | 3 (7.5) | 3 (7.5) | 0 |
| Creatinine increased | 3 (7.5) | 3 (7.5) | 0 |
| Allergic reaction | 3 (7.5) | 3 (7.5) | 0 |
| Upper respiratory infection | 3 (7.5) | 3 (7.5) | 0 |
| Skin hyperpigmentation | 2 (5.0) | 2 (5.0) | 0 |
| Skin infection | 2 (5.0) | 2 (5.0) | 0 |
| Edema limbs | 2 (5.0) | 1 (2.5) | 1 (2.5) |
| Bullous dermatitis | 1 (2.5) | 0 | 1 (2.5) |
| Adverse events | Any grade | Grade 1-2 | Grade 3-4 |
|---|---|---|---|
| Total, n (%) | 40 (100.0) | 4 (10.0) | 36 (90.0) |
| Hematological toxicity, n (%) | |||
| Leukopenia | 40 (100.0) | 8 (20.0) | 32 (80.0) |
| Neutropenia | 39 (97.5) | 4 (10.0) | 35 (87.5) |
| Anemia | 39 (97.5) | 32 (80.0) | 7 (17.5) |
| Thrombocytopenia | 15 (37.5) | 13 (32.5) | 2 (5.0) |
| Febrile neutropenia | 2 (5.0) | 0 | 2 (5.0) |
| Non-hematological toxicity, n (%) | |||
| Alopecia | 28 (70.0) | 28 (70.0) | 0 |
| Hypoalbuminemia | 21 (52.5) | 21 (52.5) | 0 |
| Pneumonitis | 21 (52.5) | 14 (35.0) | 7 (17.5) |
| ALT increased | 21 (52.5) | 19 (47.5) | 2 (5.0) |
| AST increased | 19 (47.5) | 19 (47.5) | 0 |
| Pyrexia | 19 (47.5) | 19 (47.5) | 0 |
| Mucositis | 15 (37.5) | 11 (27.5) | 4 (10.0) |
| GGT increased | 14 (35.0) | 14 (35.0) | 0 |
| Hyperglycemia | 12 (30.0) | 12 (30.0) | 0 |
| Fatigue | 11 (27.5) | 11 (27.5) | 0 |
| Cough | 11 (27.5) | 11 (27.5) | 0 |
| Hyperbilirubinemia | 8 (20.0) | 7 (17.5) | 1 (2.5) |
| Hand-foot syndrome | 7 (17.5) | 6 (15.0) | 1 (2.5) |
| Anorexia | 7 (17.5) | 7 (17.5) | 0 |
| Nausea | 6 (15.0) | 6 (15.0) | 0 |
| Hyperuricemia | 5 (12.5) | 5 (12.5) | 0 |
| Diarrhea | 5 (12.5) | 5 (12.5) | 0 |
| Constipation | 4 (10.0) | 4 (10.0) | 0 |
| Rash | 4 (10.0) | 4 (10.0) | 0 |
| Vomiting | 3 (7.5) | 3 (7.5) | 0 |
| Abdominal distension | 3 (7.5) | 3 (7.5) | 0 |
| Creatinine increased | 3 (7.5) | 3 (7.5) | 0 |
| Allergic reaction | 3 (7.5) | 3 (7.5) | 0 |
| Upper respiratory infection | 3 (7.5) | 3 (7.5) | 0 |
| Skin hyperpigmentation | 2 (5.0) | 2 (5.0) | 0 |
| Skin infection | 2 (5.0) | 2 (5.0) | 0 |
| Edema limbs | 2 (5.0) | 1 (2.5) | 1 (2.5) |
| Bullous dermatitis | 1 (2.5) | 0 | 1 (2.5) |
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transpeptidase.
Outcomes with standard CHOP or CHOP-like regimen in PTCL are poor, with an ORR of 49.0%-75.7%, PFS rates of approximately 35% at 2 years and 30.4%-43% at 5 years, and OS rates of approximately 50% at 2 years and 38.5%-48.8% at 5 years.6,12-15 By contrast, our combination regimen yielded a numerically superior ORR (82.5%), 2-year/5-year PFS (55.1% and 52.0%), 2-year OS (80.0%), and 5-year OS (62.5%) to these CHOP/CHOP-like regimens in a similar population. Additionally, although our OS data at 5 years (62.5%) were similar to the historical maximum 5-year OS rate (61%) observed from the CHOP regimen in the ECHELON-2 study,11 OS rate of up to 54.3% at 8 years and long tail in Kaplan-Meier curve further demonstrated the durable OS benefit with our modified CHOP regimen. Particularly, patients who achieved a CR at the EOT had impressive survival with an 8-year PFS and OS rates of 62.5% and 66.5%, reinforcing the potential benefit of our regimen. Even compared to a more aggressive approach with auto-SCT in the NLG-T-01 study (ORR, 82%),16 our ORR data were comparable. More notably, our regimen seems favorable over this aggressive approach with auto-SCT,16 as evidenced by the better 5-year PFS (52.0% vs 44%) and OS (62.5% vs 51%), especially when considering that no patients received consolidation with auto-SCT in our study. Besides, only a few (7.5%) patients received subsequent therapy with auto-SCT or PD-1 inhibitor while no underwent subsequent therapy with BV or allo-SCT or any consolidation/maintenance therapy further highlighted the fact that the observed long-term survival benefit was primarily attributed to our first-line regimen. Interestingly, the survival curve began to plateau after 2 years and remained flat until 8 years, the long tail in the survival curve further confirmed the robust efficacy of our regimen.
Regarding the outcomes according to histologic subtypes, the pattern of survival was consistent with previous findings that ALK-positive ALCL was associated with better outcomes than other subtypes.17 Similar to previous studies,18-20 we also revealed that patients with POD24 were associated with poor prognosis. Additionally, in contrast to previous studies in which nearly two-thirds of patients presented with POD24,18-20 only 45.5% of patients achieved POD24 with our combination treatment, further highlighting its relative effectiveness.
In terms of toxicity, compared to the CHOP regimen, our regimen showed a higher incidence of grade 3-4 neutropenia (87.5% vs 41%) and PLD-associated toxicities (eg, mucositis, hand-foot syndrome, and pneumonitis), but lower grade 3-4 febrile neutropenia (5% vs 29%),13 grade 2 alopecia (35.7% vs 92%),21 or other grade 3-4 non-hematological AEs (eg, nausea and vomiting).10,22 Nevertheless, the high incidence of pneumonitis here might be attributed to the high dose of PLD (40 mg/m2), the immune imbalance caused by neutropenia, and the use of G-CSF in our study. Our regimen also exhibited superior cardiac safety to the CHOP/CHOP-like regimen, with a lower proportion of patients experiencing an LVEF decline of ≥10% to a final LVEF of <50% (5.0% vs 22%-36%).23-25 It should be emphasized that the LVEF was assessed by radionuclide angiography here. There is evidence that radionuclide angiography has higher reproducibility than echocardiography in assessing global LVEF, and is more accurate in patients with a slight or moderate reduction in LVEF.26 Importantly, although 90% of our patients experienced grade 3-4 AEs, most of which were manageable and could be relieved by supportive care or dose reduction, and only 5 (12.5%) patients discontinued treatment due to AEs. Moreover, no life-threatening events were highlighted. Overall, our combination chemotherapy regimen demonstrated a manageable safety profile in patients with aggressive PTCL.
Several limitations need to be acknowledged in our study. Firstly, the lack of randomization makes it impossible to directly compare the efficacy and safety of our regimen with CHOP/CHOP-like or BV-containing regimens. Secondly, the open-label and single-center design might introduce a potential risk of bias. Thirdly, given the fact that PTCL comprises a heterogeneous group of NHLs, each histologic subtype had a limited sample size. Fourthly, patients enrolled in our study have relatively few poor prognostic factors according to previous studies.27,28
In summary, the long-term results from this phase 2 study showed that the combined treatment of PLD, cyclophosphamide, vincristine/vindesine, and prednisone was efficacious in patients with aggressive PTCL with a manageable safety profile, particularly a less cardiotoxicity. Based on these impressive results, this combination regimen might be a promising first-line alternative with a favorable benefit-risk balance for aggressive PTCL. Randomized, multicenter studies with a large sample size are needed to confirm our findings.
Acknowledgment
Author contributions: Jun-Ning Cao is the principal investigator.
Conflicts of interest
The authors have no relevant financial or non-financial interests to disclose.
Data availability
The data underlying this article cannot be shared publicly due to the privacy of individuals that participated in the study. The data will be shared on reasonable request to the corresponding author.
